Normal neuronal cells express the metabotropic glutamate receptor 1 (mGluR1), a G protein coupled seven transmembrane domain receptor, mGluR1 can be activated by its natural ligand, glutamate, the major neurotransmitter in the mammalian central nervous system. Targeted ectopic expression of this receptor to melanocytes transforms the cells in vivo giving rise to melanoma in mice. Studies of the signaling pathways activated by mGluR1 in melanocytes can give insights into mechanisms and molecular markers of melanoma which may be targets for therapeutic approaches. Preliminary data from gene array analysis and DNA-protein binding assays using tumor cell lines derived from these tumor-bearing transgenic mice suggest that the transcription factor nuclear factor kappa B (NF-kappaB) and other genes in this pathway may be involved in the signal transduction events activated by mGluR1. NF-KappaB has been shown to promote the transcription of anti-apoptotic genes, and in many cases it is constitutively activated in tumor cells. We also have preliminary data showing that these tumor cell lines are capable of releasing the natural ligand of mGluR1, glutamate, into the growth media. The aims of these studies are to determine if the release of glutamate by these tumor cells is able to activate mGluR1 and lead to NF-KappaB activation. We will also investigate some of the upstream kinases that may mediate the mGluR1 triggered activation of NF-KappaB in our system.